Strom Jakob O, Theodorsson Annette, Theodorsson Elvar
Department of Clinical Chemistry, Institution of Clinical and Experimental Medicine, Linköping University Hospital, Linköping, Sweden.
J Cereb Blood Flow Metab. 2009 Aug;29(8):1359-72. doi: 10.1038/jcbfm.2009.66. Epub 2009 May 20.
Numerous studies of the effects of estrogens for stroke prevention have yielded conflicting results in human and animal studies alike. We present a systematical analysis of study design and methodological differences between 66 studies where estrogens' impact on ischemic brain damage in rat models has been investigated, providing evidence that the differences in results may be explained by high estrogen doses produced by slow-release pellets. These pellets have been used in all studies showing increased neurologic damage because of estrogens. Our data indicate that the increased neurologic damage is related to the pellets' plasma concentration profile with an early, prolonged, supraphysiological peak. Neither the method of inducing the ischemic brain lesions, the choice of variables for measuring outcome, the measured plasma concentrations of estrogens at the time of ischemia nor rat population attributes (sex, strain, age, and diseases) are factors contributing to the discrepancies in results. This suggests that the effects of estrogens for stroke prevention are concentration related with a complex dose-response curve, and underscores the importance of carefully validating the experimental methods used. Future studies of hormone-replacement therapy in women may have to take dosage and administration regimens into account.
众多关于雌激素预防中风作用的研究在人体和动物研究中均得出了相互矛盾的结果。我们对66项研究进行了系统分析，这些研究调查了雌激素对大鼠模型缺血性脑损伤的影响，分析了研究设计和方法学差异，结果表明，研究结果的差异可能是由缓释微丸产生的高剂量雌激素所致。所有显示雌激素导致神经损伤增加的研究都使用了这些微丸。我们的数据表明，神经损伤增加与微丸的血浆浓度曲线有关，该曲线具有早期、持续时间长的超生理峰值。诱导缺血性脑损伤的方法、测量结果的变量选择、缺血时测量的雌激素血浆浓度以及大鼠群体属性（性别、品系、年龄和疾病）均不是导致结果差异的因素。这表明雌激素预防中风的作用与浓度相关，具有复杂的剂量反应曲线，并强调了仔细验证所用实验方法的重要性。未来关于女性激素替代疗法的研究可能必须考虑剂量和给药方案。
